Maturity onset non-insulin dependent diabetes mellitus (NIDDM) and associated preclinical conditions, such as insufficient glucose tolerance (IGT), are characterized by the diminished capacity of islet cells of the pancreas to synthesize and release sufficient insulin in response to rising blood glucose levels. Decreased sensitivity to insulin in peripheral tissues of many diabetics is also observed. New case reports of NIDDM and IGT appear to be increasing at an accelerating rate in several Western countries (Zimmer and King, World Trends in Diabetes Epidemiology, 1986). In the United States, for example, it is estimated that approximately five percent of the adult population suffers from some form of diabetic condition, with the rate of new cases increasing at about six percent per year, or approximately 600,000 new cases each year. An additional, not well-defined population exhibits preclinical symptoms such as IGT.
The management of NIDDM requires special dietary measures, and often the use of a pharmaceutical hypoglycemic agent. These agents have the ability to stimulate insulin production in the islet cells and, in conjunction with dietary measures, can help to stabilize blood sugar levels.
There are currently two chemically distinct families of oral hypoglycemic agents used in the management of NIDDM. One such family of agents, the biguanides, have been largely withdrawn from the commercial market in the United States because they have been associated with rare, but sometimes fatal, side effects. The other major family, sulfonylureas, are presently sold under approximately 100 different brand names, and as a family, constitute the only oral hypoglycemic agent in widespread use at this time in the United States. Sulfonylureas, however, fail to control hypoglycemia on initial use in approximately 30 percent to 40 percent of new cases (primary failures), and in an additional 1 to 5 percent of the new cases, they eventually lose their effectiveness (secondary failures).
There are also a variety of natural products which appear to exhibit hypoglycemic activity. These products are generally plants or plant-derived compounds, usually in the form of a somewhat crude extract. It is estimated that more than 200 species of plants exhibit hypoglycemic properties, including many common plants, such as immature bean pods, olive leaves, potatoes, wheat, celery, blackberry leaves, sugar beets, and the leaves and roots of bananas (Farnsworth and Segelman, Tile Till 57:52-55, 1971).
Other potential hypoglycemic agents have been isolated, for example, from the leaves of Aloe Aboraescens Var Natalis (Hikino et el., Int. J. Crude Drug Res. 24:183-186, 1986) and from the roots of Oryza-Sativa (Hikino et al., Planta Med. O:490-492, 1986). In addition, studies in India have shown that leaf extracts of Gynema sylvestre can prolong the life span of Alloxan-induced diabetic rats. However, use of these extracts in intact animals leads to highly variable results. These extracts also induce hypoglycemia in the Alloxan model (Srivastava et el., Int. J. Crude Drug. Res. 24:171-176, 1986).
The seeds of Eugenia Jambolana, another plant found in India, appear to exhibit hypoglycemic activity comparable to that of chlorpropamide, as determined by effects on cathepsin B (Bansal et al., Indian J. Biochem. Biophy. 18:377, 1981). Further, it has been reported that Salvia lavandulifolia possesses a slight hypoglycemic activity that is independent of the effects of insulin (Jimenez et al., Planta Med. 1:260-262, 1986). Other folklore remedies, including tea made from herbs such as Allofylus edulis (Barboza et al., Plantas Que Curan, 1985), Daucus carota and Catharanthus roseus, have been sold for the control of diabetes in South American or Southeast Asian countries.
Due to the lack of consistent clinical effectiveness for previously suggested synthetic oral hypoglycemic agents, there is a need in the art for additional, safe, oral hypoglycemic agents that provide the clinician with a wider range of options in managing maturity onset NIDDM. The present invention fills this need, and further provides other related advantages.